Angiogenic desmoplastic histopathological growth pattern as a prognostic marker of good outcome in patients with colorectal liver metastases

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Abstract
Background In patients with resectable colorectal liver metastases (CRLM), distinct histopathological growth patterns
(HGPs) develop at the interface between the tumour and surrounding tissue. The desmoplastic (d) HGP is characterised by
angiogenesis and a peripheral fibrotic rim, whereas non-angiogenic HGPs co-opt endogenous sinusoidal hepatic vasculature.
Evidence from previous studies has suggested that patients with dHGP in their CRLM have improved prognosis as compared
to patients with non-desmoplastic HGPs. However, these studies were relatively small and applied arbitrary cut-off values
for the determination of the predominant HGP. We have now investigated the prognostic effect of dHGP in a large cohort of
patients with CRLM resected either with or without neoadjuvant chemotherapy.
Methods All consecutive patients undergoing a first partial hepatectomy for CRLM between 2000 and 2015 at a tertiary
referral centre were considered for inclusion. HGPs were assessed in archival H&E stained slides according to recently
published international consensus guidelines. The dHGP was defined as desmoplastic growth being present in 100% of the
interface between the tumour and surrounding liver.
Results In total, HGPs in CRLMs from 732 patients were assessed. In the chemo-naive patient cohort (n=367), the dHGP
was present in 19% (n=68) and the non-dHGP was present in 81% (n=299) of patients. This dHGP subgroup was independently associated with good overall survival (OS) (HR: 0.39, p<0.001) and progression-free survival (PFS) (HR: 0.54,
p=0.001). All patients with any CRLM with a non-dHGP had significantly reduced OS compared to those patients with
100% dHGP, regardless of the proportion of non-dHGP (all p values≤0.001). In the neoadjuvantly treated patient cohort
(n=365), more patients were found to express dHGP (n=109, 30%) (adjusted odds ratio: 2.71, p<0.001). On univariable
analysis, dHGP was associated with better OS (HR 0.66, p=0.009) and PFS (HR 0.67, p=0.002). However, after correction for confounding by means of multivariable analysis no significant association of dHGP with OS (HR 0.92, p=0.623)
or PFS (HR 0.76, p=0.065) was seen.
Conclusions The current study demonstrates that the angiogenic dHGP in CRLM resected from chemo-naive patients acts
as a strong, positive prognostic marker, unmatched by any other prognosticator. This observation warrants the evaluation of
the clinical utility of HGPs in prospective clinical trials.